DESCRIPTION: This project proposes to use genetic techniques to gain a better understanding of zinc metabolism in the mouse. A family of genes encoding transmembrane proteins that facilitate removal of zinc from the cytoplasm has been cloned. This family includes ZnT-1, which transports zinc out of the cell; ZnT-2, which facilitates accumulation of zinc in endosomal/lysosomal compartments, and ZnT-3, which was cloned by homology to ZnT-2 and is expressed in neuronal cells that sequester zinc in synaptic vesicles. These genes may play an essential role in protecting cells from excess zinc and/or facilitating the concentration of zinc in intracellular compartments where it may serve special functions. To test these hypotheses, the expression of these transporters will be analyzed, at both the tissue and cellular level, and that information will be used to help interpret the phenotypes of mice in which each of these genes is inactivated by homologous recombination. Mice lacking both zinc transporters and metallothioneins will also be generated to help define the role of these metal-binding proteins. The most exciting outcome of these experiments may be the demonstration that zinc has important neuromodulator functions.